Alpha-1 antitrypsin deficiency is an inherited autosomal codominant genetic disorder that causes defective production of alpha 1-antitrypsin (A1AT) leading to lung and liver diseases and occurs with frequency about 1 case in 1,500 to 3,500 individuals. Alpha-1 antitrypsin deficiency most often affects persons with European ancestry worldwide.
Alpha-1 Antitrypsin (α1-antitrypsin, alpha-1 proteinase inhibitor. A1AT, or AAT) is a protease inhibitor belonging to the serpin superfamily. Normal AAT protein is primarily synthesized in the liver by hepatocytes and secreted into blood. Its physiologic function is to inhibit neutrophil proteases in order to protect host tissues from non-specific injury during periods of inflammation. The most clinically significant form of A1AT deficiency (AATD) is caused by the Z mutation. The Z mutant allele (PiZ), through a single point mutation, renders the mutant PiZ protein prone to abnormal folding in the endoplasmic reticulum of hepatocytes causing intracellular retention. The absence of circulating anti-protease activity leaves the lung vulnerable to injury by neutrophil elastase, resulting in the development of emphysema. Weekly use of AAT augmentation therapy for AATD, using purified human AAT, results in normal plasma levels of AAT and prevents lung damage in affected individuals.
While administration of purified AAT ameliorates lung damage caused by the absence of endogenously secreted AAT, AATD patients remain vulnerable to endoplasmic reticulum liver storage disease caused by the deposition of excessive abnormally folded AAT protein. Twelve to fifteen percent of patients with AATD also develop liver disease, which can be severe or fatal, even in infancy. The intracellular accumulation in hepatocytes of AAT protein in AATD patients induces liver cell damage and death, and chronic liver injury. Clinical presentations include chronic hepatitis, cirrhosis, hepatocellular carcinoma, transaminitis, cholestasis, fibrosis, and even fulminant hepatic failure.
There is currently no specific treatment to prevent the onset or slow the progression of liver disease due to AATD. Because liver damage resulting from AATD occurs through a gain-of-function mechanism, inhibition or AAT gene expression would be useful in preventing accumulation of the AAT protein in the liver, thereby providing a therapeutic treatment for AATD. Double-stranded RNA molecules (dsRNA) and other RNAi triggers have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi). The invention provides AAT RNA interference (RNAi) triggers and compositions thereof for inhibiting the expression of the AAT gene in vivo. The invention also provides methods of using the AAT RNAi triggers for treating AATD and conditions and diseases caused by AATD, such as chronic hepatitis, cirrhosis, hepatocellular carcinoma, and fulminant hepatic failure.